Changes in effective and lethal doses of intravenous anesthetics and lidocaine when used in combination in mice

We studied the interactions between a local anesthetic agent, lidocaine, and two general anesthetic drugs, propofol and ketamine, in mice. We used two end points: hypnosis, reflected by loss of the righting reflex, and death. The ED50 for hypnosis and the LD50 were determined for each drug separately, and a dose-response curve was prepared for each drug, using combinations of propofol-lidocane and ketamine-lidocaine at three different dose ratios. Probit and isobolographic analyses revealed supra-additive (synergistic) interactions between lidocaine and each of the other anesthetic agents regarding both the effective dose and the lethal dose. No significant difference was found between propofol and ketamine regarding the supraadditive effect.     

丙泊酚和依托咪酯用于雄性 SD 大鼠麻醉效果的比较

摘要： 目的 序贯法测定雄性 SD 大鼠静脉麻醉丙泊酚和依托咪酯的 95%有效剂量 （ED95）, 比较 2 种麻醉药物的效能和麻醉维持时间。方法 28 只雄性 SD 大鼠随机分成丙泊酚组和依托咪酯组, 每组 14 只。以翻正反射作为意识的判定指标。根据公式 Y=Ymin+ （Ymax-Ymin ） / ［1+10log （ED50-X） ×m ］ 拟合大鼠翻正反射消失的剂量-反应性曲线。分别测定丙泊酚和依托咪酯的 ED95 和大鼠静脉注射等效剂量的 2 种药物后麻醉持续时间。结果 测得两组 SD 大鼠丙泊酚 ED95 为 9 mg/kg, 依托咪酯 ED95 为 1.5 mg/kg, 丙泊酚与依托咪酯 ED95 的比值为 6。丙泊酚组大鼠麻醉维持时间 （465.6±18.5） s, 依托咪酯组麻醉维持时间 （233.7±9.3） s, 两组差异有统计学意义 （P＜0.05）。结论 以 ED95 为等效剂量, 丙泊酚组麻醉维持时间长于依托咪酯组。     

Antagonism of the behavioral effects of ethanol by naltrexone in BALB/c,C57BL/6, and DBA/2 mice

The effects of naltrexone on the increase in locomotor activity induced by a low dose (1.35 g/kg IP) of ethanol and on the duration of loss of righting reflex after a high dose (3.5 g/kg) of ethanol were studied in BALB/c, DBA/2, and C57BL/6 mice. Ethanol increased locomotor activity in DBA and BALB mice, but not in C57BL mice. Naltrexone, at a dose of 0.1 mg/kg, antagonized the ethanol-induced increase in locomotion similarly in DBA and BALB mice. The duration of loss of righting reflex was, however, differentially affected in all three strains by naltrexone. The BALB mice affected in all three strains by naltrexone. The BALB mice were the most sensitive strain (1 mg/kg naltrexone significantly counteracted ethanol hypnosis), the C57BL mice were intermediate (8 mg/kg naltrexone required to antagonize this effect of ethanol), and the DBA mice were least sensitive (no effect evident even at the highest dose of 8 mg/kg) to naltrexone. Thus, naltrexone could antagonize the behavioral effects of a low and high dose of ethanol, but the three strains, which differ in their behavioral response to ethanol, also were differentially sensitive to the effect of naltrexone in reversing ethanol-induced hypnosis and ethanol-induced changes in locomotor activity.     

咪达唑仑和芬太尼的相互作用

目的:观察芬太尼与咪达唑仑合用对小鼠学习记忆和镇痛、催眠作用的影响.方法:将小鼠分为:咪达唑仑组(M)、芬太尼组(F)和咪达唑仑+芬太尼组(MF).用避暗实验观察3组的学习记忆的功能;用甩尾实验和扭体实验观察3组的镇痛作用;用翻正反射实验观察3组的催眠作用.结果:与M组、F组相比,MF组进入暗室的潜伏期和错误次数均相似(P>0.05);MF组痛阈明显升高、扭体次数明显减少(P<0.01);MF组的翻正反射持续时间延长.结论:咪达唑仑和芬太尼两药合用镇痛作用与催眠作用增强,但学习记忆无明显改变.     

山莨菪碱对地西泮小鼠催眠和镇痛作用的影响

目的观察山莨菪碱对地西泮催眠和镇痛作用的影响。方法用翻正反射法观察山莨菪碱对地西泮小鼠睡眠时间的影响;用甩尾法实验观察山莨菪碱对地西泮小鼠甩尾潜伏期的影响。结果在翻正反射实验中,山莨菪碱可缩短地西泮小鼠的睡眠时间(P<0.05);在甩尾法实验中,山莨菪碱对地西泮小鼠的甩尾潜伏期无影响(P>0.05),但二者合用有协同镇痛的趋势。结论山莨菪碱可缩短地西泮的睡眠时间;山莨菪碱与地西泮合用有协同镇痛的趋势。     

中央内侧丘脑核中 NMDA 受体参与丙泊酚致意识消失的作用

目的 探讨中央内侧丘脑核（CMT）中 N-甲基-D-天门冬氨酸（NMDA）受体在全身麻醉意识消失中的作用。方法 60 只大鼠微注射模型随机均分为 4 组： NMDA10 mmol/L 组、 NMDA20 mmol/L 组、 NMDA40 mmol/L 组及对照组 （C 组）, 丙泊酚麻醉后分别于前 3 组 CMT 内微量泵注 10、 20 和 40 mmol/L 的 NMDA 以及等体积生理盐水 （C组）。观察微注射后自主体动反应的发生率以及翻正反射恢复时间, 并通过组织学对微注射位点进行定位。结果 当注射位点在 CMT 中时, 与 C 组相比, 各浓度 NMDA 组大鼠麻醉后翻正反射恢复时间均明显缩短; 其中 NMDA20 mmol/L 与 40 mmol/L 组恢复时间短于 NMDA10 mmol/L 组, 且 NMDA20 mmol/L 与 40 mmol/L 组大鼠麻醉中自主体动的发生率显著高于 C 组 （均 P < 0.05）。当注射部位在 CMT 外时, 各浓度 NMDA 组翻正反射恢复时间均明显长于注射部位在 CMT 内者（P < 0.05）, 而各组间比较自主体动发生率与翻正反射恢复时间均无明显差异（P＞0.05）。结论 CMT 中的NMDA 受体参与了丙泊酚所导致的全身麻醉效应。     

Potentiation of barbiturate- and halothane-induced hypnosis after probenecid or sulfinpyrazone pretreatment

The uricosuric agent, probenecid, when administered prior to systemic administration of pentobarbital led to a decreased latency, to loss of righting reflex and to a potentiation of the duration of hypnosis. This potentiation was dose-related and doses of probenecid below 50mg/kg (i.p.) were without effect. Pretreatment of rats with sulfinpyrazone, another uricosuric agent, yielded similar results. Pre-treatment of animals with probenecid shortened the latency to onset of hypnosis induced by halothane (i.p.) and increased the duration of loss of righting reflex, 3-fold. Both sulfinpyrazone and probenecid, administered prior to 1.0% inhalation halothane exposure, shortened the latency to onset of hypnosis in doses as small as 10mg/kg, much less than the doses required to affect significantly pentobarbital-induced hypnosis. The results, as yet, do not indicate a plausible mechanism of action, but do expose a potentially useful drug interaction which may be of clinical use.     

Seasonal and sex influences on ketamine-induced analgesia and catalepsy in the rat; a possible role for melatonin

Data from this laboratory on ketamine-induced analgesia and catalepsy in rats revealed that factors other than dose modified the difference in the latency of the tail flick response (TFLD), a measure of analgesia, and the duration of the loss of the righting reflex (DLRR), a measure of catalepsy. Untreated female rats showed a longer latency than males in their response to a noxious stimulus at midnight, but not at noon. Females also showed a longer loss of righting reflex response to ketamine than did males, whether at noon or midnight; the loss of righting reflex at night was augmented in both. Although females showed analgesia with administration of ketamine at doses smaller than those which induced catatonia, males showed no analgesia without catatonia and comparable loss of the righting reflex occurred at doses much larger than for females. There was a 3-fold increase in the latency of the tail flick response and loss of righting reflex during the winter, as compared with summer, for females treated with ketamine; males showed a similar variation in the loss of righting reflex. Since analgesia is produced by both melatonin and ketamine, and since ketamine appears to share opiate receptors with an endogenous ligand, beta-endorphin, a role was sought for the pineal and melatonin in the variation of responsiveness to ketamine. Pinealectomized rats failed to show augmentation of the loss of righting reflex induced by ketamine at night and mice showed a seasonal variation in the analgesia induced by melatonin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxygen toxicity: Protection of the lung by bacterial lipopolysaccharide (endotoxin)

Adult rats were exposed to > 95% O₂ for a 72-hr period and treated with small dosages of endotoxin (250 μg/kg/day, 1/100th LD50) during the exposure or with a single dose of endotoxin (500 μg/kg) administered just prior to the hyperoxic exposure. Endotoxin treatment increased the survival rate in hyperoxia from 12/44 (27%) for untreated rats to 38/40 (95%) for the treated animals (p < 0.05). In addition, the endotoxin-treated animals had significantly decreased O₂-induced pulmonary edema and pleural fluid accumulation compared to the untreated rats (p < 0.05). Histological examination by light microscopy demonstrated marked lung damage in the untreated. hyperoxia-exposed animal lungs (perivascular, interstitial, and alveolar edema and lung hemorrhage) but only minimal changes in the lungs of the endotoxin-treated group of animals exposed to hyperoxia. Transmission electron microscopy showed a protective action of endotoxin treatment on the pulmonary capillary endothelium, compatible with the decreased exudative changes (edema) observed in the O₂-exposed endotoxin-treated lungs. Indomethacin and methylprednisolone pretreatment failed to alter the protective action of endotoxin versus pulmonary O₂ toxicity.     

Comparison of isomers of ketamine on catalepsy in the rat and electrical activity of the brain and behavior in the cat

The present study compared the relative potency and efficacy of the two isomers of ketamine on the duration of catalepsy (loss of righting reflex) in female rats and on the behavior and electroencephalogram of cats. In the rat, at small doses, the S(+) isomer was more potent than the R(-) isomer or racemic ketamine, while at larger doses, the S(+) isomer and the racemate were equipotent and the R(-) isomer was significantly less potent. Tolerance developed rapidly to the effects of either isomer and both were equally cross-tolerant to racemic ketamine. Sub-effective doses of morphine significantly increased the potency of S(+), R(-) and racemic ketamine on the duration of catalepsy. Sub-effective doses of either isomer augmented the duration of catalepsy, induced by small doses of morphine, but reduced that of large doses. In cats, there was a parallel time course and progression of behavioral and electroencephalographic states in response to equal total doses of either racemic ketamine, an artificial 50:50 mixture of S(+) and R(-) isomers, or the S(+) isomer alone; approximately equivalent effects required twice the dose of the R(-) isomer. It is concluded that there is a common site of action for the two isomers, but there is also a stereospecific difference in potency, as regards the induction of catalepsy in the rat and behavioral and electroencephalographic effects in the cat. Stereospecificity was not apparent in the development of tolerance, cross-tolerance or the augmentation of the response to morphine.     

异丙嗪对异氟烷小鼠镇痛、催眠、遗忘作用和治疗指数的影响

目的观察异丙嗪对异氟烷镇痛、催眠、遗忘作用和治疗指数的影响。方法用热板法和扭体法观察异丙嗪对异氟烷镇痛作用的影响,翻正反射法观察异丙嗪对异氟烷小鼠睡眠时间的影响,Morris水迷宫法观察异丙嗪对异氟烷小鼠遗忘作用的影响,并用序贯法观察异丙嗪对异氟烷小鼠催眠ED50、LD50的影响。结果在热板法和扭体法实验中,异丙嗪增强了异氟烷的镇痛作用(P<0.05或P<0.01);在翻正反射实验中,异丙嗪可延长异氟烷小鼠的睡眠时间(P<0.01);在水迷宫实验中,异丙嗪组和异氟烷组的平均逃避潜伏期均少于两药合用组(P<0.05或P<0.01),第3象限停留时间均多于两药合用组(P<0.01或P<0.05),异氟烷组原平台穿越次数多于合用组(P<0.05);异丙嗪可降低异氟烷小鼠的催眠ED50(P<0.01),而对其LD50无影响(P>0.05)。结论异丙嗪可以增强异氟烷的镇痛、催眠和遗忘作用,并可以提高异氟烷的治疗指数。     

异丙酚麻醉前后鼠脑ATPase活性的动态变化

目的　观察异丙酚 (propofol)麻醉不同时期大鼠大脑皮层、海马和脑干Na+ ,K+ ATPase、Ca2 + ATPase活性的动态变化 ,探讨异丙酚的全麻作用机制。方法　♀SD大鼠 40只 ,按麻醉不同时期随机分为 5组。分别在腹腔注射 (ip) 10ml·kg-1生理盐水 2min后 (对照组 ) ,ip异丙酚 10 0mg·kg-12min后、翻正反射消失前 (诱导期组 ) ,翻正反射消失后 3 0min(麻醉期组 ) ,翻正反射刚恢复、尚未完全清醒时 (恢复期组 ) ,动物完全清醒后 (清醒期组 ) ,断头取脑。用分光光度法测定各脑区Na+ ,K+ ATP酶和Ca2 + ATP酶的活性。结果　与对照组比较 ,异丙酚 10 0mg·kg-1使大脑皮层、海马和脑干的Na+ ,K+ ATP酶和Ca2 + ATP酶的活性在诱导期即降低 ,麻醉期进一步降低 (P <0 0 5 ,P <0 0 1) ,恢复期开始升高 ,但仍低于对照组 ,清醒期基本恢复到对照组水平。结论　异丙酚 10 0mg·kg-1能明显抑制脑ATP酶活性且与行为变化平行 ,提示ATP酶可能在异丙酚的全麻机制中发挥重要作用     

术中保温对老年病人全麻苏醒时间及苏醒期丙泊酚效应室浓度的影响

目的 分析讨论术中保温对老年病人全麻苏醒时间及苏醒期丙泊酚效应室浓度的影响,以期为临床提供指导性依据.方法 选取全麻下行开腹胃肠外科手术的老年病人78例为研究对象,年龄均为60岁以上,参照双盲随机法将病人分为对照组与研究组,每组39例.对照组仅予以液体输入与铺巾覆盖,研究组则采取液体输入、腹腔冲洗液体加温以及暖风毯覆盖等术中保温措施,记录比较两组病人从麻醉开始到手术完成不同时间点的食管温度、平均动脉压(MAP)及丙泊酚效应室浓度的动态变化,偏相关分析MAP、丙泊酚效应室浓度与食管温度的相关性,同时比较两组病人苏醒时间与效应室浓度.结果 两组病人在T0、T1的食管温度方面差异无统计学意义(P>0.05),研究组T2~T6的食管温度均明显高于对照组,差异有统计学意义(P<0.05),另两组不同时间点的MAP均差异无统计学意义(P>0.05).研究组与对照组T0~T5丙泊酚效应室浓度比较差异无统计学意义(P>0.05),研究组T6丙泊酚效应室浓度高于对照组,差异有统计学意义(P<0.05);MAP与食管温度偏回归系数0.074,两者无明显相关性.丙泊酚效应室浓度与食管温度偏回归系数0.109,两者有较弱的正相关关系,即食管温度越高,则丙泊酚效应室浓度越高;两组病人丙泊酚停药时脑电双频指数(BIS)差异无统计学意义(P>0.05),而在停药时BIS值≥80的恢复时间及其效应室浓度则差异有统计学意义(P<0.05).研究组睁眼、应答及拔管时间均显著低于对照组(P<0.05).结论 行全麻开腹手术治疗的老年病人实施术中保温有助于维持病人全麻下正常体温,缩短术后苏醒时间,加快病人术后苏醒,临床应用价值较高.     

Protective action of the serine protease inhibitor N-tosyl-L-lysine chloromethyl ketone (TLCK) against acute soman poisoning

Soman-poisoned rats display cholinergic crisis, a systemic mast cell degranulation characteristic of anaphylactic reactions and an excitotoxin-like sequential seizure and neuronal degeneration. The protection of guinea pigs from soman lethality by prophylactic administration of the serine protease inhibitor suramin suggests a possible proteolytic component in soman poisoning. The present study tested the effect of N-tosyl-L-lysine chloromethyl ketone (TLCK), an inhibitor of trypsin-like serine proteases, on soman-induced toxic signs (convulsions, righting reflex) and survival time. Nine control guinea pigs receiving 2 x LD(50) (56 microg kg(-1), s.c.) of soman immediately followed by a therapeutic dose of atropine sulfate (17.4 mg kg(-1) i.m.) experienced severe convulsions, and 8/9 lost the righting reflex. Six of these nine animals expired within 65 min; the three remaining animals survived 24 h to termination of the experiment. When a second group of animals were given TLCK (12 mg kg(-1), i.p.) 30 min prior to a 2 x LD(50) soman challenge and atropine-sulfate therapy, 5/9 experienced convulsions and only 3/9 lost the righting reflex. All nine animals survived beyond 4 h, with six surviving to 24 h. Compared with soman controls, prophylaxis with TLCK significantly prevented the loss of righting reflex (P = 0.05) and enhanced 4-h survival (P = 0.005). Although, convulsions were reduced and 24-h survival was improved in TLCK-treated animals, these results were not statistically significant. The protection from soman toxicity by chemically distinct protease inhibitors such as suramin and TLCK suggests a role for pathological proteolytic pathways in soman intoxication.     

Kinetics of Drug Action in Disease States. XXXI. Effect of Experimental Hyperthyroidism on the Hypnotic Activity of a Benzodiazepine (Oxazepam) in Rats

This investigation was designed to determine the effect of experimental hyperthyroidism on the hypnotic activity of a benzodiazepine and on the binding characteristics of the benzodiazepine receptor complex. Rats were made hyperthyroid by subcutaneous implantation of slow release pellets containing L-thyroxine. This treatment produced the characteristic symptoms of hyperthyroidism: increased serum thyroxine concentrations, increased heart weight and body temperature, and decreased serum protein concentrations. The hyperthyroid rats and a parallel group of normal animals (with drug-free pellets implanted subcutaneously) were slowly infused intravenously with oxazepam until they lost their righting reflex. The hyperthyroid rats required a significantly larger dose of the benzodiazepine and their total serum and cerebrospinal fluid concentrations of oxazepam (but not the serum concentration of free drug and the brain concentration) at the onset of loss of the righting reflex were modestly but statistically significantly lower than those of the normal rats. The receptor density and affinity for diazepam in hyperthyroid rats were not significantly different from those of the normal animals. Hyperthyroidism apparently affects the pharmacokinetics of oxazepam but has, at best, only a small effect on the pharmacodynamics (hypnotic activity) of the drug.     

Increased responsiveness to ethanol with advancing age in rats

Male CD strain rats of three different ages (young—5 months; middle—15; old—27 months) were tested for their responsiveness to doses of ethanol sufficient to produce hypothermia or hypnosis. Comparison dosages of ethanol across age groups were based upon the estimated equivalent dilution of the drug into the body water compartments of subjects. In the hypnosis study, there were no statistically significant differences among the groups with regard to the time elapsed until the righting reflex was lost or in total sleep time. However, old animals recovered the righting reflex in the presence of lower blood ethanol concentrations than those observed for young and middle animals, suggesting a greater sensitivity of target tissues to the hypnotic effects of ethanol in old rats. The responsiveness of old rats to the hypothermic effect of ethanol was greater than that of younger rats only when the experiment was conducted at an ambient room temperature of 10°C.     

Intravenous midazolam significantly enhances the lethal effect of thiopental but not that of ketamine in mice

Intravenous (i.v.) drug combinations are used in clinical anaesthesia in order to combine the desired effects and minimize toxicity from large doses of single agents. This fundamental assumption has not been systematically evaluated. We examined its validity by testing the influence of midazolam on the lethal effect of i.v. thiopental and ketamine in mice. Dose-response curves were constructed for the lethal effect of i.v. thiopental and ketamine, and for the loss of righting reflex effect by midazolam, in sexually mature male ICR mice weighing 20-40 g. For each curve, six or seven groups of eight to 10 mice each were used. A quarter of the median effective dose (ED50) for loss of righting reflex by midazolam was combined with the two other drugs to deduce dose-response curves for the lethal effect of the combinations. The ED50 for loss of righting reflex by i.v. midazolam was 43.5 mg x kg(-1) (95% confidence interval [CI], 40.4-46.5). The median lethal dose (LD 50) of i.v. thiopental was 50.6 mg x kg(-1) (95% CI, 50.0-54.9) and that of ketamine 42.9 mg x kg(-1) (95% CI, 32.3-52). In the presence of 10 mg x kg(-1) midazolam, the LD50 of thiopental was reduced to 20 mg x kg(-1) (17.7-22.2), but that of ketamine remained 44.4 mg x kg(-1) (37.7-54.9). Midazolam increased the lethal effect of thiopental 2.5-fold, but did not affect that of ketamine. Interactions at the toxic level between commonly used anaesthetic agents may differ from those at the hypnotic or analgesic levels, which should prompt evaluation of such combinations before their introduction to routine clinical use.     

Biopharmaceutics: Formulation-dependent Pharmacokinetics and Pharmacodynamics of Propofol in Rats

Propofol, a highly lipophilic anaesthetic, is commercially formulated as a lipid emulsion (diprivan) for intravenous use. This formulation is characterized by rapid onset and offset of effect after rapid intravenous administration and an effect-site equilibration half-life (t 1/2 k_E0) of 1.7min in rats. Paradoxically these characteristics are usually associated with relatively water-soluble anaesthetics. To test the influence of the formulation on propofol pharmacokinetics, effect-site equilibration kinetics and pharmacodynamics we performed a pharmacokinetic-pharmacodynamic study of propofol in chronically instrumented rats after administration in a lipid-free formulation. In this report we present the results of this study and compare these results with previous data obtained with rats receiving propofol in the emulsion formulation. Compared with the emulsion formulation the distribution volumes (Vd_c and Vd_ss) were significantly higher but the t 1/2 k_E0 (2.0 min) was similar for the lipid-free formulation. The concentration-effect relationship was biphasic. Propofol effect-site concentrations required to achieve 50% activation, peak activation, 50% inhibition of peak activation effect and maximum inhibition were significantly lower, indicating a higher apparent steady-state potency for the lipid-free formulation compared with the emulsion formulation. The evanescent characteristics of propofol's effect-time-course disappeared when the anaesthetic was administered in the lipid-free formulation. These results suggest that the nature of the formulation can profoundly influence the clinical characteristics of intravenously administered drugs by modifying the pharmacokinetics or pharmacodynamics or both.